Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].[Li][CH2:9][CH2:10][CH2:11]C.BrCC=C>C1COCC1>[CH2:11]([CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][C:2]1=[O:7])[CH:10]=[CH2:9]
Reactant: O=C1CCCCN1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCC1CCCNC1=O
Temperature: -75 °C
Reaction time: 1 h

Procedure:
To a solution of piperidin-2-one (0.5 g, 5.0 mmol, 1 equiv) in dry THF (10.0 mL) was added nBuLi (4.2 ml, 10.5 mmol, 2.1 equiv) dropwise at 0° C. The mixture was then cooled to −75° C. and excess 3-bromoprop-1-ene was added to the mixture. The reaction mixture was kept at −78° C. for 1 h, quenched with NH4Cl solution and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give the desired product, which was directly used for the next step without further purification.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:12])[C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[CH3:13][C:14]([CH3:18])([CH3:17])[CH:15]=O.C(OC)(OC)OC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1CCCC1=O.C(O)(=O)C>[CH2:13]([N:3]1[CH2:4][CH2:5][C:6]2[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2]1)[C:14]([CH3:18])([CH3:17])[CH3:15]
Reactant: Oc1cccc2c1CCNCC2
Reactant: CC(C)(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CC(C)(C)CN1CCc2cccc(O)c2CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol (see Demarinis et al. J. Med. Chem. 1984, 27, 918-921) (60 mg, 0.37 mmol), trimethylacetaldehyde (400 μL, 3.7 mmol), trimethyl orthoformate (390 μL, 3.7 mmol) and glacial acetic acid (40 μL) in 1-methyl-2-pyrolidinone (2.5 mL) was stirred at rt for 2.5 h. Sodium triacetoxyborohydride (388 mg, 1.8 mmol) was then added and the mixture was stirred at room temperature for 16 h. The mixture was then loaded on top of a silica gel-SCX (sulfonic acid) column and eluted first with methanol, then with 2 M ammonia in methanol. The latter fraction was evaporated and the resulting 3-neopentyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ol was used in the next step without further purification. (M+H)+=234.0.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N:13]2[CH:17]=[CH:16][CH:15]=[CH:14]2)[CH:8]=1)(=O)=O.[SH:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=[O:23].CS([O-])(=O)=O.OC1C=C(C=CC=1)C=O>>[N:13]1([C:9]2[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=2)[CH2:6][S:18][C:19]2[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=2)[CH2:22][OH:23])[CH:14]=[CH:15][CH:16]=[CH:17]1
Reactant: CS(=O)(=O)OCc1cccc(-n2cccc2)c1
Reactant: O=Cc1cccc(S)c1
Agent: CS(=O)(=O)[O-]
Agent: O=Cc1cccc(O)c1
Product: OCc1cccc(SCc2cccc(-n3cccc3)c2)c1

Procedure:
3-[3-(3-thienyl)benzyloxy]benzyl alcohol, 3-[4-(3-thienyl)-2-thienylmethylthio]benzyl alcohol, 3-[3-(5-oxazolyl)benzylthio]benzyl alcohol, 3-[3-(5-oxazolyl)benzylthio]benzyl alcohol and 3-[3-(1-pyrrolyl) benzyloxy]benzyl alcohol are obtained by performing the same reaction as in Referential Example 57 except that instead of the starting 3-(1-pyrrolyl)benzyl methanesulfonate and/or 3-mercaptobenzaldehyde, the corresponding methanesulfonate and/or 3-hydroxybenzaldehyde are used.
Reaction SMILES: Cl.[NH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=1)=[NH:4].C(=O)([O-])[O-].[K+].[K+].[Cl:23][C:24]1[CH:48]=[CH:47][C:27]2[C:28](=O)[C:29](=[CH:42]N(C)C)[CH2:30][N:31]=[C:32]([C:33]3[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[F:41])[C:26]=2[CH:25]=1.Cl>O.CO>[Cl:23][C:24]1[CH:48]=[CH:47][C:27]2[C:28]3[N:2]=[C:3]([NH:5][C:6]4[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([O:15][CH3:16])[CH:7]=4)[N:4]=[CH:42][C:29]=3[CH2:30][N:31]=[C:32]([C:33]3[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[F:41])[C:26]=2[CH:25]=1
Reactant: COc1cccc(F)c1C1=NCC(=CN(C)C)C(=O)c2ccc(Cl)cc21
Reactant: COc1cc(NC(=N)N)ccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2C(c2c(F)cccc2OC)=NC3)ccc1C(=O)O
Temperature: 52.5 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Into a reactor was added 6 (3.81 kg, 15.5 mol), potassium carbonate (4.3 kg, 31.1 mol), 9 (5.27 kg, 14.1 mol) and methanol (63 L). The suspension was warmed to 50 to 55° C. and stirred for a minimum of 24 h until ≧96.0% conversion was obtained by HPLC analysis. Methanol (10 L) and water (37 L) were added while maintaining the temperature between 50 and 55° C. The pH of the mixture was adjusted to 3.0 to 4.0 using 7% w/w HCl (prepared from 7.0 kg of concentrated HCl and 24 L of water) while maintaining the temperature between 50 and 55° C. The suspension was cooled to 20 to 25° C. over a minimum of 1 h and stirred for at least 60 min. The resulting suspension was filtered and washed with water (2×26.3 L) at 50 to 55° C. and methanol (2×10 L) at 20 to 25° C. The wet cake was dried at 45 to 50° C. under vacuum to provide 5.85 kg (80% yield) of Formula (II). 1H NMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.22 (s, 1H), 8.72 (s, 1H), 8.29 (d, J=8.8 Hz, 1H), 7.95 (s, 1H), 7.80 (dd, J=2.4, 8.9 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.39 (m, 3H), 7.21 (s, 1H), 6.89 (s, 2H), 3.82 (s, 6H); MS (ESI) m/z MS (ESI) m/z 517.2 (M−H+, 45%).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][N:3]=1.[CH3:8][O:9][C:10]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:11]=1[NH2:12]>>[CH3:8][O:9][C:10]1[CH:16]=[C:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][C:11]=1[NH2:12]
Reactant: Cn1ncnc1Br
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Product: COc1cc(-c2ncnn2C)ccc1N

Procedure:
The title compound was prepared according to the method described for Preparation 158 using 5-bromo-1-methyl-1H-1,2,4-triazole and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline. The residue was purified using Biotage silica gel column chromatography eluting with EtOAc.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.FC(F)(F)S(O[C:18]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:19]=1[CH2:20][C@H:21]([N:28]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:22][O:23]2)(=O)=O>>[CH2:36]([N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:21]1[CH2:20][C:19]2[C:24](=[CH:25][CH:26]=[CH:27][C:18]=2[C:6]2[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[O:23][CH2:22]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: O=S(=O)(Oc1cccc2c1C[C@H](N(Cc1ccccc1)Cc1ccccc1)CO2)C(F)(F)F
Product: COc1ccc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)cn1
Yield: 84 %

Procedure:
The title compound was synthesized as described for Intermediate example I-2 in 84% yield, starting from 2-methoxy-5-pyridineboronic acid (1.7 equiv) and (3S)-3-(dibenzylamino)-3,4-dihydro-2H-chromen-5-yl trifluoromethanesulfonate; MS (ESI) m/z 437[M+H+].
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[C:2]([NH2:4])=[NH:3].[CH3:15][S:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[C:23](OC1C=CC([N+]([O-])=O)=CC=1)=[O:24])(=[O:18])=[O:17].CS(NC1C=C(C=CC=1)C(O)=O)(=O)=O.[N+](C1C=CC(O)=CC=1)([O-])=O.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.C(Cl)[Cl:85]>CO>[ClH:85].[CH3:15][S:16]([NH:19][C:20]1[CH:21]=[C:22]([CH:35]=[CH:36][CH:37]=1)[C:23]([NH:14][CH2:13][CH2:12][S:11][CH2:10][C:8]1[N:9]=[C:5]([NH:1][C:2]([NH2:4])=[NH:3])[S:6][CH:7]=1)=[O:24])(=[O:18])=[O:17]
Reactant: CS(=O)(=O)Nc1cccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: ClCCl
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)Nc1cccc(C(=O)O)c1
Agent: O=[N+]([O-])c1ccc(O)cc1
Solvent: CO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(C(=O)NCCSCc2csc(NC(=N)N)n2)c1
Product: Cl
Temperature: 40 °C
Reaction time: 4 h

Procedure:
A solution of 0.015 mol of 2-(2-guanidinothiazol-4-ylmethylthio)ethylamine, 0.015 mol of 4-nitrophenyl 3-methanesulfonamidobenzoate (m.p. 162°-164° C., prepared from 3-methanesulfonamidobenzoic acid and 4-nitrophenol in methylene chloride in the presence of dicyclohexylcarbodiimide) and 0.035 mol of triethylamine in 150 ml of methanol is heated at 40° C. under stirring for 4 hours. Then the solvent is evaporated under reduced pressure and the residue is taken up with 20 ml of water and 100 ml of ethyl acetate. The organic phase is dried on anhydrous sodium sulfate, the solvent is evaporated under reduced pressure and the residue is dissolved in 50 ml of warm ethyl acetate. The solution is filtered and the filtrate is acidified with hydrogen chloride in isopropanol. Thus, 3-methanesulfonamido-N-[2-(2-guanidinothiazol-4-ylmethylthio)ethyl]benzamide hydrochloride is obtained, which, after crystallization from 20 ml of water gives 2 g of the monohydrate, SR 57938 A; m.p. 117°-120° C.
Reaction SMILES: C([O:4][CH2:5][C:6](=[CH2:8])[CH3:7])(=O)C.[C:9]([O:12][CH2:13]C=C)(=[O:11])[CH3:10]>>[CH2:5]([OH:4])[C:6](=[CH2:7])[CH3:8].[C:9]([O:12][CH3:13])(=[O:11])[CH3:10]
Reactant: C=C(C)COC(C)=O
Reactant: C=CCOC(C)=O
Product: C=C(C)CO
Product: COC(C)=O
Yield: 93 %
Yield: 99 %

Procedure:
The tube, catalyst and general procedure described in Example 2 were employed, with 57.0 g of methallyl acetate substituted for the allyl acetate. The effluent in this case was composed of 12.5 g of unconverted methallyl acetate (22% recovery), 27.8 g of methallyl alcohol (99% yield based on 78% conversion), 26.8 g of methyl acetate (93% yield) and the excess methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(N(C)C)=C(C)C.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.COC(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]([N:32]=[N+:33]=[N-:34])=[O:15])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Br:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2Br)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N=[N+]=[N-])(c2ccccc2Br)CC1
Reaction time: 0.75 h
Yield: 82.7 %

Procedure:
To a solution of 2.00 g (5.20 mmol) 4-(2-bromo-phenyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester in 26 ml dichloromethane were added 0.76 ml (5.73 mmol) 1-chloro-N,N,2-trimethylpropenylamine at room temperature. After stirring for 45 min the reaction mixture was concentrated in vacuo. The residual oil was redissolved in 26 ml dry N,N-dimethylformamide and treated with 0.51 g (7.8 mmol) sodium azide. After stirring for 1 h the reaction mixture was diluted with 200 ml tert-butyl methyl ether and washed with 0.5 M aqueous sodium carbonate solution (2×50 ml). The combined aqueous layers were extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were washed with water (1×50 ml) and brine (1×50 ml), dried over sodium sulfate and concentrated in vacuo to give the crude title compound (1.76 g, 83%) as a light yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>CS(C)=O>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=4)[C:12]#[N:13])=[CH:4][CH:3]=3)[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: CS(C)=O
Product: N#Cc1ccc(-c2ccc(N3CCN(c4cccc(Cl)c4)CC3)cc2)[nH]c1=O

Procedure:
From 12.9 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 23.7 g. of N-(m-chlorophenyl)-piperazine in 180 ml. of dimethyl sulfoxide; there is obtained 6-[p-[4-(m-chlorophenyl)-1-piperazinyl]phenyl]-1,2-dihydro-2-oxonicotinonitrile.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C@H:6]([C:10]([OH:12])=[O:11])[CH:7]([CH3:9])[CH3:8]>C1(C)C=CC=CC=1.C1COCC1>[CH:7]([C@H:6]1[C:10](=[O:11])[O:12][C:1](=[O:2])[NH:5]1)([CH3:9])[CH3:8]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)[C@@H]1NC(=O)OC1=O
Temperature: 55 °C
Yield: 47.32 %

Procedure:
30.4 ml (57.47 mmol, 1.08 eq.) of a 20% solution of phosgene in toluene were added slowly at r.t. to a stirred solution of 6.26 g (53.44 mmol) L-valine (81a) in 63 ml dry THF. After the complete addition the mixture was heated at 55° C. for 4 h. Then a stream of nitrogen was bubbled through the solution and passed after that through a 1M aq. NaOH-solution for 20 min. before the solvent was evaporated. Recrystallization of the obtained residue from PE/Ether (2:1) yielded 3.62 g (25.29 mmol, 47.32%) (S)-4-Isopropyl-oxazolidine-2,5-dione (86) as a white solid.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13](Cl)[C:12]([Cl:19])=[N:11]2)=[O:7]>CO>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([NH:2][NH2:3])[C:12]([Cl:19])=[N:11]2)=[O:7]
Reactant: NN
Reactant: COC(=O)c1ccc2nc(Cl)c(Cl)nc2c1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2nc(NN)c(Cl)nc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Hydrazine monohydrate (0.26 mL) was added dropwise to a suspension of 2,3-dichloro-quinoxaline-6-carboxylic acid methyl ester (1.2 g) in methanol (10 mL) at −10° C. After three hrs. at this temperature, an additional portion of hydrazine monohydrate (0.26 mL) was added, and the resulting mixture was stirred at 0° C. for three hrs., and then for one hr. at 23° C. The suspension was filtered, and the solids were washed with MeOH. Flash column chromatography provided a residue that was recrystallized from MeOH to provide 3-chloro-2-hydrazino-quinoxaline-6-carboxylic acid methyl ester as a yellow solid. MS (M+H)+=253.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])(=O)C.[Na+].[Br:17]Br.C([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[C:10]([Br:17])=[C:9]([F:11])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: BrBr
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(F)c(Br)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a mixture of 2-amino-6-fluorobenzothiazole (245 mg, 1.46 mmol) and sodium acetate (244 mg, 2.97 mmol) in acetic acid (1.60 mL) was added bromine (1.0 M in AcOH, 1.60 mL, 1.60 mmol) at RT. The mixture was stirred at RT for 1 h. The mixture was then treated with aqueous Na2CO3 until pH=7 and extracted with EtOAc (3×30 mL). The combined organic fractions were washed with water (2×20 mL) and brine (30 mL), dried over MgSO4, filtered, and concentrated. Purification by ISCO chromatography (0 to 30% EtOAc:heptane) afforded 357 mg of the impure title compound as a dark brown solid (357 mg). MS (ESI): 246.92, 248.93 [M+H]+; HPLC tR=1.25 min (TOF: polar—3 min).
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[C:35]([O:41][CH3:42])[CH:34]=1)=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:42][O:41][C:35]1[CH:34]=[C:33]([C:31](=[O:32])[CH2:30][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:28][C:6]=3[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8]2=[O:12])[CH:38]=[CH:37][C:36]=1[O:39][CH3:40]
Reactant: COc1ccc(C(=O)CBr)cc1OC
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(OC)c(OC)c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 2-bromo-1-(3,4-dimethoxyphenyl)ethanone (0.8 g) and N,N-dimethylformamide (25 mL) was added 60% sodium hydride (0.16 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (1.25 g, 86%).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([O:9]CC)=O.[CH3:12][C:13]([CH3:15])=[O:14].CC(C)([O-])C.[K+].C(O)(=O)C>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7](=[O:9])[CH2:12][C:13](=[O:14])[CH3:15]
Reactant: CCOC(=O)c1occc1Br
Reactant: CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)CC(=O)c1occc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-bromofuran-2-carboxylate (16.2 g) and acetone (5.14 mL) in toluene (250 mL) was added potassium tert-butoxide (15.7 g) at 0° C. portionwise. The reaction mixture was stirred at room temperature for 2 hr, and acetic acid (8.01 mL) and water (250 mL) were added. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from hexane/ethyl acetate to give the title compound (10.9 g, enol/diketone=88/12).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1Br.O.CC(O)=O>C1(C)C=CC=CC=1.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 500 mL three-necked round-bottom flask fitted with an overhead mechanical stirrer, and reflux condenser was charged with 4,5-dibromofuran-2-carboxylic acid (34.3 g, 127 mmol), H2O (100 mL), and HOAc (25 mL). The third neck of the flask was stoppered and the suspension was heated to reflux with a temperature controlled heating mantle held at 125-130° C. Zn dust (15.0 g, 229 mmol) (previously ground in a mortar and pestle to break up lumps) was added portionwise over 50 minutes. Subsequent portions are added after most of the previously added portion has disappeared. After the first portions of the Zn were added, all of the 4,5-dibromofuran-2-carboxylic acid dissolved to give a pale brown solution. Near the end of the Zn addition a white solid began to appear in the reaction flask. Ten minutes after the conclusion of the zinc addition a thick white slurry had formed. HPLC analysis of the reaction slurry after 15 minutes indicated nearly complete consumption of the starting 4,5-dibromofuran-2-carboxylic acid and conversion to the desired product. After 40 minutes, heating was discontinued, and the white slurry was allowed to cool to ambient temperature. After cooling to ambient temperature the reaction slurry was diluted with cold H2O (100 mL), cooled in an ice bath, and then filtered. The solids were rinsed with cold H2O, dried on the filter, and the resulting damp solids were dissolved in warm acetone (1.6 L). The resulting solution was filtered to remove residual zinc dust, and then concentrated under reduced pressure to afford a white solid. The resulting solid was broken up with a spatula and pumped down under high vacuum to afford an off-white powder. 1H NMR analysis of the material (DMSO-d6) showed it to be quite pure but to contain H2O. The solids were suspended in toluene (˜1 L) and heated to reflux in a flask fitted with a condenser and a Dean-Stark trap. The suspension was heated at reflux for ˜1 hour at which time less than 1 mL of H2O had collected in the trap. The suspension was cooled, and concentrated under reduced pressure to afford 4-bromo furan-2-carboxylic acid as a-white powdery solid. 1H-NMR (400 MHz, DMSOd6): δ 7.96 (1H, d, J=0.8 Hz), 7.04 (1H, d, J=0.8 Hz).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[F:31][C:32]([F:42])([F:41])[CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[F:31][C:32]([F:41])([F:42])[CH2:33][C:34]1[CH:40]=[CH:39][C:37]([N:38]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: Nc1ccc(CC(F)(F)F)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: O=C1N(c2ccc(CC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1ccccc1OC(F)(F)F)CC2

Procedure:
Off-white solid. MS (ESI): 537.12 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-(2,2,2-trifluoro-ethyl)-aniline.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][CH:29]=1)[CH2:5][NH:6][C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]3[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]3)[CH:14]=2)[CH:10]=[N:9][CH:8]=1.C(O)(=O)C.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.CN1C(=O)CCC1>[CH2:34]([NH:26][C@H:23]1[CH2:22][CH2:21][C@H:20]([NH:19][C:15]2[CH:14]=[C:13]([C:11]3[CH:10]=[N:9][CH:8]=[C:7]([NH:6][CH2:5][C:4]4[CH:27]=[CH:28][CH:29]=[C:2]([F:1])[CH:3]=4)[N:12]=3)[CH:18]=[CH:17][N:16]=2)[CH2:25][CH2:24]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cncc(NCc4cccc(F)c4)n3)ccn2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: Fc1cccc(CNc2cncc(-c3ccnc(N[C@H]4CC[C@H](NCc5ccccc5)CC4)c3)n2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To trans-N1-(4-(6-(3-fluorobenzylamino)pyrazin-2-yl)pyridin-2-yl)cyclohexane-1,4-diamine (19 mg, 0.048 mmol) was added NMP (0.6 ml), acetic acid (0.042 ml, 0.726 mmol) and benzaldehyde (10.27 mg, 0.097 mmol). The resulting reaction mixture was stirred overnight at ambient temperature. To the stirred reaction mixture was added sodium triacetoxyborohydride (41.0 mg, 0.194 mmol) and the resulting mixture was stirred overnight (24 hours) at ambient temperature. To the reaction mixture then was added additional sodium triacetoxyborohydride (21.0 mg, 0.099 mmol) and the resulting mixture was stirred for an additional 2 more hours. To the crude mixture then was added 0.8 ml of DMSO, filtered and purified by prep LC. After lyphilization, 7.0 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 483.2 (MH+), retention time=0.65 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.35-1.51 (m, 2H) 1.51-1.69 (m, 2H) 2.04-2.36 (m, 4H) 3.08-3.18 (m, 1H) 3.56-3.70 (m, 1H) 4.16 (s, 2H) 4.60 (s, 2H) 6.82-6.93 (m, 1H) 7.03 (d, J=9.67 Hz, 1H) 7.11 (d, J=7.62 Hz, 1H) 7.19-7.29 (m, 1H) 7.32 (d, J=6.74 Hz, 1H) 7.35-7.46 (m, 5H) 7.54 (s, 1H) 7.80 (d, J=6.74 Hz, 1H) 7.97 (s, 1H) 8.25 (s, 1H)